Sublingual and buccal film compositions

ABSTRACT

The present invention relates to products and methods for treatment of narcotic dependence in a user. The invention more particularly relates to self-supporting dosage forms which provide an active agent for treating narcotic dependence while providing sufficient buccal adhesion of the dosage form.

FIELD OF THE INVENTION

The present invention relates to compositions, methods of manufacture,products and methods of use relating to films containing therapeuticactives. The invention more particularly relates to self-supporting filmdosage forms which provide a therapeutically effective dosage,essentially matching that of currently-marketed tablets containing thesame active. Such compositions are particularly useful for treatingnarcotic dependence while providing sufficient buccal adhesion of thedosage form.

BACKGROUND OF THE RELATED TECHNOLOGY

Oral administration of two therapeutic actives in a single dosage formcan be complex if the intention is to have one active absorbed into thebody and the other active remain substantially unabsorbed. For example,one active may be relatively soluble in the mouth at one pH, and theother active may be relatively insoluble at the same pH. Moreover, theabsorption kinetics of each therapeutic agent may be substantiallydifferent due to differing absorption of the charged and unchargedspecies. These factors represent some of the challenges in appropriatelyco-administering therapeutic agents.

Co-administration of therapeutic agents has many applications. Amongsuch areas of treatment include treating individuals who suffer fromnarcotic dependence. Such individuals have a tendency to suffer fromserious physical dependence on the narcotic, resulting in potentiallydangerous withdrawal effects when the narcotic is not administered tothe individual. In order to help individuals addicted to narcotics, itis known to provide a reduced level of a drug, which provides an effectof satisfying the body's urge for the narcotic, but does not provide the“high” that is provided by the misuse of the narcotic. The drug providedmay be an agonist or a partial agonist, which provides a reducedsensation and may help lower dependence on the drug. However, eventhough these drugs provide only a low level of euphoric effect, they arecapable of being abused by the individuals parenterally. In such cases,it is desirable to provide a combination of the drug with a second drug,which may decrease the likelihood of diversion and abuse of the firstdrug. For example, it is known to provide a dosage of an antagonist incombination with the agonist or partial agonist. The narcotic antagonistbinds to a receptor in the brain to block the receptor, thus reducingthe effect of the agonist.

One such combination of drugs has been marketed under the trade nameSuboxone® as an orally ingestible tablet. However, such combinations intablet form have the potential for abuse. In some instances, the patientwho has been provided the drug may store the tablet in his mouth withoutswallowing the tablet, then later extract the agonist from the tabletand inject the drug into an individual's body. Although certainantagonists (such as highly water-soluble antagonists) may be used tohelp reduce the ability to separate the agonist, the potential for abusestill exists. It is desired to provide a dosage that cannot be easilyremoved from the mouth once it has been administered.

There is currently a need for an orally dissolvable film dosage formthat provides the desired absorption levels of the agonist andantagonist, while providing an adhesive effect in the mouth, renderingit difficult to remove once placed in the mouth, thereby making abuse ofthe agonist difficult.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, there is provided a filmdosage composition including: a polymeric carrier matrix; atherapeutically effective amount of buprenorphine or a pharmaceuticallyacceptable salt thereof, a therapeutically effective amount of naloxoneor a pharmaceutically acceptable salt thereof; and a buffer in an amountto provide a pH of the composition of a value sufficient to optimizeabsorption of the buprenorphine.

In another embodiment of the present invention, there is provided a filmdosage composition including: a polymeric carrier matrix; atherapeutically effective amount of buprenorphine or a pharmaceuticallyacceptable salt thereof, a therapeutically effective amount of naloxoneor a pharmaceutically acceptable salt thereof; and a buffer in an amountsufficient to inhibit the absorption of the naloxone when administeredorally.

In still other embodiments, there may be provided a film dosagecomposition including: a polymeric carrier matrix; a therapeuticallyeffective amount of buprenorphine or a pharmaceutically acceptable saltthereof, a therapeutically effective amount of naloxone or apharmaceutically acceptable salt thereof; and a buffering system; wherethe buffering system includes a buffer capacity sufficient to maintainthe ionization of naloxone during the time which the composition is inthe oral cavity of a user.

In another embodiment of the invention, there is provided a method oftreating narcotic dependence of a user, including the steps of:providing a composition including: a polymeric carrier matrix; atherapeutically effective amount of buprenorphine or a pharmaceuticallyacceptable salt thereof, a therapeutically effective amount of naloxoneor a pharmaceutically acceptable salt thereof, and a buffer in an amountto provide a pH of the composition of a value sufficient to optimizeabsorption of the buprenorphine; and administering the composition tothe oral cavity of a user.

In still another embodiment of the invention, there is provided aprocess of forming a film dosage composition including the steps of:casting a film-forming composition, the film-forming compositionincluding: a polymeric carrier matrix; a therapeutically effectiveamount of buprenorphine or a pharmaceutically acceptable salt thereof, atherapeutically effective amount of naloxone or a pharmaceuticallyacceptable salt thereof, and a buffer in an amount to provide a pH ofthe composition of a value sufficient to optimize absorption of thebuprenorphine and drying the film-forming composition to form aself-supporting film dosage composition.

In another embodiment, there is provided a film dosage compositionincluding a therapeutically sufficient amount of buprenorphine or apharmaceutically acceptable salt thereof and a therapeuticallysufficient amount of naloxone or a pharmaceutically acceptable saltthereof, the film dosage composition having a bioequivalent releaseprofile as compared to a Suboxone® tablet containing about 2 times theamount of buprenorphine or a pharmaceutically acceptable salt thereof.

Still other embodiments of the present invention provide an orallydissolving film formulation including buprenorphine and naloxone, wherethe formulation provides an in-vivo plasma profile having a Cmax ofbetween about 0.624 ng/ml and about 5.638 ng/ml for buprenorphine and anin-vivo plasma profile having a Cmax of between about 41.04 pg/ml toabout 323.75 pg/ml for naloxone.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions

As used herein, the term Cmax refers to the mean maximum plasmaconcentration after administration of the composition to a humansubject. As also used herein, the term AUC refers to the mean area underthe plasma concentration-time curve value after administration of thecompositions formed herein. As will be set forth in more detail below,the term “optimizing the absorption” does not refer to reaching themaximum absorption of the composition, and rather refers to reaching theoptimum level of absorption at a pH of about 2 to about 4. The “optimum”absorption may be, for example, a level that provides a bioequivalentabsorption as administration of the currently available Suboxone®tablet. An “optimum” Cmax of buprenorphine is about 0.67 to about 5.36mg/ml at dosages of from 2-16 mg buprenorphine at a given pH. Similarly,an “optimum” AUC of buprenorphine may be about 7.43 to about 59.46hr*ng/ml at dosages of from 2-16 mg buprenorphine at a given pH. As willbe described in more detail below, it has been surprisingly discoveredthat the absorption of one particular agonist, buprenorphine, canprovide an optimum absorption at a pH of about 2-4 as well as about5.5-6.5. Thus, one may “optimize” the absorption of buprenorphine byproviding a pH of about 2-4 or about 5.5-6.5.

“Maximizing the absorption” refers to the maximum in vivo absorptionvalues achieved at a pH of about 4 to about 9.

The term “local pH” refers to the pH of the region of the carrier matriximmediately surrounding the active agent as the matrix hydrates and/ordissolves, for example, in the mouth of the user.

By “inhibiting” the absorption of an active, it is meant achieving ascomplete an ionization state of the active as possible, such that littleto none of the active is measurably absorbable. For example, at a pH of3-3.5, the Cmax of an active such as naloxone for dosage of 0.5 mg to4.0 mg ranges from 32.5 to 260 pg/ml, and an AUC of naloxone for dosageof 0.5 mg to 4.0 mg ranges from 90.55 to 724.4 hr*pg/ml. It isunderstood that at a pH lower than 3.0, further ionization would beexpected and thus result in lower absorption.

The term “bioequivalent” means obtaining 80% to 125% of the Cmax and AUCvalues for a given active in a different product. For example, assumingCmax and AUC values of buprenorphine for a commercially-availableSuboxone® tablet (containing 2 mg buprenorphine and 0.5 mg naloxone) are0.780 ng/ml and 6.789 hr*ng/ml, respectively, a bioequivalent productwould have a Cmax of buprenorphine in the range of 0.624-0.975 ng/ml,and an AUC value of buprenorphine of 5.431-8.486 hr*ng/ml.

It will be understood that the term “film” includes thin films andsheets, in any shape, including rectangular, square, or other desiredshape. The films described herein may be any desired thickness and sizesuch that it may be placed into the oral cavity of the user. Forexample, the films may have a relatively thin thickness of from about0.1 to about 10 mils, or they may have a somewhat thicker thickness offrom about 10 to about 30 mils. For some films, the thickness may beeven larger, i.e., greater than about 30 mils. Films may be in a singlelayer or they may be multi-layered, including laminated films.

Oral dissolving films generally fall into three main classes: fastdissolving, moderate dissolving and slow dissolving. Fast dissolvingfilms generally dissolve in about 1 second to about 30 seconds in themouth. Moderate dissolving films generally dissolve in about 1 to about30 minutes in the mouth, and slow dissolving films generally dissolve inmore than 30 minutes in the mouth. Fast dissolving films may consist oflow molecular weight hydrophilic polymers (i.e., polymers having amolecular weight between about 1,000 to 9,000, or polymers having amolecular weight up to 200,000). In contrast, slow dissolving filmsgenerally have high molecular weight polymers (i.e., having a molecularweight in the millions).

Moderate dissolving films tend to fall in between the fast and slowdissolving films. Moderate dissolving films dissolve rather quickly, butalso have a good level of mucoadhesion. Moderate dissolving films arealso flexible, quickly wettable, and are typically non-irritating to theuser. For the instant invention, it is preferable to use films that fallbetween the categories of fast dissolving and moderate dissolving. Suchmoderate dissolving films provide a quick enough dissolution rate, mostdesirably between about 1 minute and about 20 minutes, while providingan acceptable mucoadhesion level such that the film is not easilyremovable once it is placed in the oral cavity of the user.

Inventive films described herein may include one or more agonists orpartial agonists used for the treatment of drug addiction. As usedherein, the term “agonist” refers to a chemical substance that iscapable of providing a physiological response or activity in the body ofthe user. The films described herein may further include one or moreantagonists. As used herein, the term “antagonist” refers to anychemical substance that acts within the body of the user to reduce thephysiological activity of another chemical substance. In someembodiments, an antagonist used herein may act to reduce and/or blockthe physiological activity of the agonist. The actives may bewater-soluble, or they may be water-insoluble. As used herein, the term“water-soluble” refers to substances that are at least partiallydissolvable in a solvent, including but not limited to water. The term“water-soluble” does not necessarily mean that the substance is 100%dissolvable in the solvent. The term “water-insoluble” refers tosubstances that are not dissolvable in a solvent, including but notlimited to water. Solvents may include water, or alternatively mayinclude other polar solvents by themselves or in combination with water.

Inventive Films

The present invention relates to methods of treating narcotic dependencein an individual. More desirably, the invention relates to the treatmentof opioid dependence in an individual, while using a formulation anddelivery that hinders misuse of the narcotic. Currently, treatment ofopioid dependence is aided by administration of Suboxone®, which is anorally dissolvable tablet. This tablet which provides a combination ofbuprenorphine (an opioid agonist) and naloxone (an opioid antagonist).Therefore, the present invention provides a method of treating narcoticdependence by providing an orally dissolvable film dosage, whichprovides a bioequivalent effect to Suboxone®. The film dosage preferablyprovides buccal adhesion while it is in the user's mouth, rendering itdifficult to remove after placement.

The film dosage composition preferably includes a polymeric carriermatrix. Any desired polymeric carrier matrix may be used, provided thatit is orally dissolvable. Desirably, the dosage should have enoughbioadhesion to not be easily removed and it should form a gel likestructure when administered. The orally consumable films are preferablymoderate-dissolving in the oral cavity and particularly suitable fordelivery of actives, although both fast and sustained releasecompositions are also among the various embodiments contemplated.

The films used in the pharmaceutical products may be produced by acombination of at least one polymer and a solvent, optionally includingother fillers known in the art. The solvent may be water, a polarorganic solvent including, but not limited to, ethanol, isopropanol,acetone, or any combination thereof. In some embodiments, the solventmay be a non-polar organic solvent, such as methylene chloride. The filmmay be prepared by utilizing a selected casting or deposition method anda controlled drying process. For example, the film may be preparedthrough controlled drying processes, which include application of heatand/or radiation energy to the wet film matrix to form a visco-elasticstructure, thereby controlling the uniformity of content of the film.Such processes are described in more detail in commonly assigned U.S.application Ser. No. 10/074,272, filed on Feb. 14, 2002, and publishedas U.S. Patent Publication No. 2003/0107149 A1, the contents of whichare incorporated herein by reference in their entirety. Alternatively,the films may be extruded as described in commonly assigned U.S.application Ser. No. 10/856,176, filed on May 28, 2004, and published asU.S. Patent Publication No. 2005/0037055 A1, the contents of which areincorporated herein by reference in their entirety.

The polymer included in the films may be water-soluble, water-swellable,water-insoluble, or a combination of one or more either water-soluble,water-swellable or water-insoluble polymers. The polymer may includecellulose or a cellulose derivative. Specific examples of usefulwater-soluble polymers include, but are not limited to, polyethyleneoxide, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose,polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum,tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin,and combinations thereof. Specific examples of useful water-insolublepolymers include, but are not limited to, ethyl cellulose, hydroxypropylethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and combinations thereof. For higher dosages, it maybe desirable to incorporate a polymer that provides a high level ofviscosity as compared to lower dosages.

As used herein the phrase “water-soluble polymer” and variants thereofrefer to a polymer that is at least partially soluble in water, anddesirably fully or predominantly soluble in water, or absorbs water.Polymers that absorb water are often referred to as beingwater-swellable polymers. The materials useful with the presentinvention may be water-soluble or water-swellable at room temperatureand other temperatures, such as temperatures exceeding room temperature.Moreover, the materials may be water-soluble or water-swellable atpressures less than atmospheric pressure. Desirably, the water-solublepolymers are water-soluble or water-swellable having at least 20 percentby weight water uptake. Water-swellable polymers having a 25 or greaterpercent by weight water uptake are also useful. In some embodiments,films formed from such water-soluble polymers may be sufficientlywater-soluble to be dissolvable upon contact with bodily fluids.

Other polymers useful for incorporation into the films includebiodegradable polymers, copolymers, block polymers and combinationsthereof. It is understood that the term “biodegradable” is intended toinclude materials that chemically degrade, as opposed to materials thatphysically break apart (i.e., bioerodable materials). Among the knownuseful polymers or polymer classes which meet the above criteria are:poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanes,polyoxalates, poly(α-esters), polyanhydrides, polyacetates,polycaprolactones, poly(orthoesters), polyamino acids,polyaminocarbonates, polyurethanes, polycarbonates, polyamides,poly(alkyl cyanoacrylates), and mixtures and copolymers thereof.Additional useful polymers include, stereopolymers of L- and D-lacticacid, copolymers of bis(p-carboxyphenoxy)propane acid and sebacic acid,sebacic acid copolymers, copolymers of caprolactone, poly(lacticacid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers ofpolyurethane and (poly(lactic acid), copolymers of polyurethane andpoly(lactic acid), copolymers of α-amino acids, copolymers of α-aminoacids and caproic acid, copolymers of α-benzyl glutamate andpolyethylene glycol, copolymers of succinate and poly(glycols),polyphosphazene, polyhydroxy-alkanoates and mixtures thereof. Binary andternary systems are contemplated.

Other specific polymers useful include those marketed under the Medisorband Biodel trademarks. The Medisorb materials are marketed by the DupontCompany of Wilmington, Del. and are generically identified as a“lactide/glycolide co-polymer” containing “propanoic acid,2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid.” Foursuch polymers include lactide/glycolide 100 L, believed to be 100%lactide having a melting point within the range of 338°-347° F.(170°-175° C.); lactide/glycolide 100 L, believed to be 100% glycolidehaving a melting point within the range of 437°-455° F. (225°-235° C.);lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolidewith a melting point within the range of 338°-347° F. (170°-175° C.);and lactide/glycolide 50/50, believed to be a copolymer of 50% lactideand 50% glycolide with a melting point within the range of 338°-347° F.(170°-175° C.).

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

Although a variety of different polymers may be used, it is desired toselect polymers that provide mucoadhesive properties to the film, aswell as a desired dissolution and/or disintegration rate. In particular,the time period for which it is desired to maintain the film in contactwith the mucosal tissue depends on the type of active contained in thecomposition. Some actives may only require a few minutes for deliverythrough the mucosal tissue, whereas other actives may require up toseveral hours or even longer. Accordingly, in some embodiments, one ormore water-soluble polymers, as described above, may be used to form thefilm. In other embodiments, however, it may be desirable to usecombinations of water-soluble polymers and polymers that arewater-swellable, water-insoluble and/or biodegradable, as providedabove. The inclusion of one or more polymers that are water-swellable,water-insoluble and/or biodegradable may provide films with slowerdissolution or disintegration rates than films formed from water-solublepolymers alone. As such, the film may adhere to the mucosal tissue forlonger periods or time, such as up to several hours, which may bedesirable for delivery of certain active components.

Desirably, the individual film dosage has a small size, which is betweenabout 0.5-1 inch by about 0.5-1 inch. Most preferably, the film dosageis about 0.75 inches×0.5 inches. The film dosage should have goodadhesion when placed in the buccal cavity or in the sublingual region ofthe user. Further, the film dosage should disperse and dissolve at amoderate rate, most desirably dispersing within about 1 minute anddissolving within about 3 minutes. In some embodiments the film dosagemay be capable of dispersing and dissolving at a rate of between about 1to about 1.5 minutes.

For instance, in some embodiments, the films may include polyethyleneoxide alone or in combination with a second polymer component. Thesecond polymer may be another water-soluble polymer, a water-swellablepolymer, a water-insoluble polymer, a biodegradable polymer or anycombination thereof. Suitable water-soluble polymers include, withoutlimitation, any of those provided above. In some embodiments, thewater-soluble polymer may include hydrophilic cellulosic polymers, suchas hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose. Inaccordance with some embodiments, polyethylene oxide may range fromabout 20% to 100% by weight in the polymer component, more specificallyabout 30% to about 70% by weight, and even more specifically about 40%to about 60% by weight. In some embodiments, one or morewater-swellable, water-insoluble and/or biodegradable polymers also maybe included in the polyethylene oxide-based film. Any of thewater-swellable, water-insoluble or biodegradable polymers providedabove may be employed. The second polymer component may be employed inamounts of about 0% to about 80% by weight in the polymer component,more specifically about 30% to about 70% by weight, and even morespecifically about 40% to about 60% by weight.

The molecular weight of the polyethylene oxide also may be varied. Insome embodiments, high molecular weight polyethylene oxide, such asabout 4 million, may be desired to increase mucoadhesivity of the film.In some other embodiments, the molecular weight may range from about100,000 to 900,000, more specifically from about 100,000 to 600,000, andeven more specifically from about 100,000 to 300,000. In someembodiments, it may be desirable to combine high molecular weight(600,000 to 900,000) with low molecular weight (100,000 to 300,000)polyethylene oxide in the polymer component.

A variety of optional components and fillers also may be added to thefilms. These may include, without limitation: surfactants; plasticizers;polyalcohols; anti-foaming agents, such as silicone-containingcompounds, which promote a smoother film surface by releasing oxygenfrom the film; thermo-setting gels such as pectin, carageenan, andgelatin, which help in maintaining the dispersion of components;inclusion compounds, such as cyclodextrins and caged molecules; coloringagents; and flavors. In some embodiments, more than one activecomponents may be included in the film.

Additives may be included in the films. Examples of classes of additivesinclude excipients, lubricants, buffering agents, stabilizers, blowingagents, pigments, coloring agents, fillers, bulking agents, sweeteningagents, flavoring agents, fragrances, release modifiers, adjuvants,plasticizers, flow accelerators, mold release agents, polyols,granulating agents, diluents, binders, buffers, absorbents, glidants,adhesives, anti-adherents, acidulants, softeners, resins, demulcents,solvents, surfactants, emulsifiers, elastomers and mixtures thereof.These additives may be added with the active ingredient(s).

Useful additives include, for example, gelatin, vegetable proteins suchas sunflower protein, soybean proteins, cotton seed proteins, peanutproteins, grape seed proteins, whey proteins, whey protein isolates,blood proteins, egg proteins, acrylated proteins, water-solublepolysaccharides such as alginates, carrageenans, guar gum, agar-agar,xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gumkaraya, gum tragancanth), pectin, water-soluble derivatives ofcellulose: alkylcelluloses hydroxyalkylcelluloses andhydroxyalkylalkylcelluloses, such as methylcelulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose, hydroxypropylmethylcellulose,hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcelluloseesters such as cellulose acetate phthalate (CAP),hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses,carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such ascarboxymethylcellulose and their alkali metal salts; water-solublesynthetic polymers such as polyacrylic acids and polyacrylic acidesters, polymethacrylic acids and polymethacrylic acid esters,polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP),polyvinylpyrrolidone (PVP), PVY/vinyl acetate copolymer, andpolycrotonic acids; also suitable are phthalated gelatin, gelatinsuccinate, crosslinked gelatin, shellac, water-soluble chemicalderivatives of starch, cationically modified acrylates and methacrylatespossessing, for example, a tertiary or quaternary amino group, such asthe diethylaminoethyl group, which may be quaternized if desired; andother similar polymers.

Such extenders may optionally be added in any desired amount desirablywithin the range of up to about 80%, desirably about 3% to 50% and moredesirably within the range of 3% to 20% based on the weight of all filmcomponents.

Further additives may flow agents and opacifiers, such as the oxides ofmagnesium aluminum, silicon, titanium, etc. desirably in a concentrationrange of about 0.02% to about 3% by weight and desirably about 0.02% toabout 1% based on the weight of all film components.

Further examples of additives are plasticizers which includepolyalkylene oxides, such as polyethylene glycols, polypropyleneglycols, polyethylene-propylene glycols, organic plasticizers with lowmolecular weights, such as glycerol, glycerol monoacetate, diacetate ortriacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol,sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributylcitrate, and the like, added in concentrations ranging from about 0.5%to about 30%, and desirably ranging from about 0.5% to about 20% basedon the weight of the polymer.

There may further be added compounds to improve the texture propertiesof the starch material such as animal or vegetable fats, desirably intheir hydrogenated form, especially those which are solid at roomtemperature. These fats desirably have a melting point of 50° C. orhigher. Preferred are tri-glycerides with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀-and C₂₂-fatty acids. These fats can be added alone without addingextenders or plasticizers and can be advantageously added alone ortogether with mono- and/or di-glycerides or phosphatides, especiallylecithin. The mono- and di-glycerides are desirably derived from thetypes of fats described above, i.e. with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀-and C₂₂-fatty acids.

The total amounts used of the fats, mono-, di-glycerides and/orlecithins are up to about 5% and preferably within the range of about0.5% to about 2% by weight of the total film composition.

It further may be useful to add silicon dioxide, calcium silicate, ortitanium dioxide in a concentration of about 0.02% to about 1% by weightof the total composition. These compounds act as flow agents andopacifiers.

Lecithin is one surface active agent for use in the films describedherein. Lecithin may be included in the feedstock in an amount of fromabout 0.25% to about 2.00% by weight. Other surface active agents, i.e.surfactants, include, but are not limited to, cetyl alcohol, sodiumlauryl sulfate, the Spans™ and Tweens™ which are commercially availablefrom ICI Americas, Inc. Ethoxylated oils, including ethoxylated castoroils, such as Cremophor EL which is commercially available from BASF,are also useful. Carbowax™ is yet another modifier which is very usefulin the present invention. Tweens™ or combinations of surface activeagents may be used to achieve the desired hydrophilic-lipophilic balance(“HLB”). The present invention, however, does not require the use of asurfactant and films or film-forming compositions of the presentinvention may be essentially free of a surfactant while still providingthe desirable uniformity features of the present invention.

Other ingredients include binders which contribute to the ease offormation and general quality of the films. Non-limiting examples ofbinders include starches, pregelatinize starches, gelatin,polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone, andpolyvinylalcohols.

Further potential additives include solubility enhancing agents, such assubstances that form inclusion compounds with active components. Suchagents may be useful in improving the properties of very insolubleand/or unstable actives. In general, these substances aredoughnut-shaped molecules with hydrophobic internal cavities andhydrophilic exteriors. Insoluble and/or instable actives may fit withinthe hydrophobic cavity, thereby producing an inclusion complex, which issoluble in water. Accordingly, the formation of the inclusion complexpermits very insoluble and/or instable actives to be dissolved in water.A particularly desirable example of such agents are cyclodextrins, whichare cyclic carbohydrates derived from starch. Other similar substances,however, are considered well within the scope of the present invention.

Suitable coloring agents include food, drug and cosmetic colors (FD&C),drug and cosmetic colors (D&C), or external drug and cosmetic colors(Ext. D&C). These colors are dyes, their corresponding lakes, andcertain natural and derived colorants. Lakes are dyes absorbed onaluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments are preferred, such as the oxides or iron or titanium, theseoxides, being added in concentrations ranging from about 0.001 to about10%, and preferably about 0.5 to about 3%, based on the weight of allthe components.

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof. A non-limiting representative list of examples includes mintoils, cocoa, and citrus oils such as lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot or other fruitflavors.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and combinationsthereof, saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,xylitol, and the like. Also contemplated are hydrogenated starchhydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used.

Anti-foaming and/or de-foaming components may also be used with thefilms. These components aid in the removal of air, such as entrappedair, from the film-forming compositions. Such entrapped air may lead tonon-uniform films. Simethicone is one particularly useful anti-foamingand/or de-foaming agent. The present invention, however, is not solimited and other anti-foam and/or de-foaming agents may suitable beused.

As a related matter, simethicone and related agents may be employed fordensification purposes. More specifically, such agents may facilitatethe removal of voids, air, moisture, and similar undesired components,thereby providing denser, and thus more uniform films. Agents orcomponents which perform this function can be referred to asdensification or densifying agents. As described above, entrapped air orundesired components may lead to non-uniform films.

Simethicone is generally used in the medical field as a treatment forgas or colic in babies. Simethicone is a mixture of fully methylatedlinear siloxane polymers containing repeating units ofpolydimethylsiloxane which is stabilized with trimethylsiloxyend-blocking unites, and silicon dioxide. It usually contains 90.5-99%polymethylsiloxane and 4-7% silicon dioxide. The mixture is a gray,translucent, viscous fluid which is insoluble in water.

When dispersed in water, simethicone will spread across the surface,forming a thin film of low surface tension. In this way, simethiconereduces the surface tension of bubbles air located in the solution, suchas foam bubbles, causing their collapse. The function of simethiconemimics the dual action of oil and alcohol in water. For example, in anoily solution any trapped air bubbles will ascend to the surface anddissipate more quickly and easily, because an oily liquid has a lighterdensity compared to a water solution. On the other hand, analcohol/water mixture is known to lower water density as well as lowerthe water's surface tension. So, any air bubbles trapped inside thismixture solution will also be easily dissipated. Simethicone solutionprovides both of these advantages. It lowers the surface energy of anyair bubbles that trapped inside the aqueous solution, as well aslowering the surface tension of the aqueous solution. As the result ofthis unique functionality, simethicone has an excellent anti-foamingproperty that can be used for physiological processes (anti-gas instomach) as well as any for external processes that require the removalof air bubbles from a product.

In order to prevent the formation of air bubbles in the films, themixing step can be performed under vacuum. However, as soon as themixing step is completed, and the film solution is returned to thenormal atmosphere condition, air will be re-introduced into or contactedwith the mixture. In many cases, tiny air bubbles will be again trappedinside this polymeric viscous solution. The incorporation of simethiconeinto the film-forming composition either substantially reduces oreliminates the formation of air bubbles.

Simethicone may be added to the film-forming mixture as an anti-foamingagent in an amount from about 0.01 weight percent to about 5.0 weightpercent, more desirably from about 0.05 weight percent to about 2.5weight percent, and most desirably from about 0.1 weight percent toabout 1.0 weight percent.

Any other optional components described in commonly assigned U.S. Pat.No. 7,425,292 and U.S. application Ser. No. 10/856,176, referred toabove, also may be included in the films described herein.

When the dosage form includes at least one antagonist, it may be desiredto control the release of the antagonist, so as to delay or whollyprevent the release of the antagonist from the dosage when taken orally.Desirably, the dosage form is a self-supporting film composition, whichis placed into the oral cavity of the user. In a dosage form that is tobe placed in the oral cavity, it is desired to absorb the agonistbuccally, so as to provide rapid integration of the agonist into thebody of the user. At the same time, it may be desired to prevent orreduce absorption of any antagonist buccally, thereby allowing theantagonist to be swallowed and destroyed in the stomach. Reducing theabsorption of an antagonist may be achieved via physical means, such asby encapsulating the antagonist in a material that blocks absorption. Itis desired, however, to reduce the absorption of the antagonist bychemical means, such as by controlling the local pH of the dosage.

It has been found that by controlling the local pH of the dosage form,the release and/or absorption of the actives therein may be controlled.For example, in a dosage that includes an amount of an agonist, thelocal pH may be controlled to a level that maximizes its release and/orabsorption into the oral cavity of the user. In dosages incorporating anamount of an agonist and an amount of an antagonist, the local pH may becontrolled to a level that maximizes the release and/or absorption ofthe agonist while simultaneously minimizing the release and/orabsorption of the antagonist.

The dosage form preferably includes a combination of a partial agonistand an antagonist, while the dosage has a controlled pH. In oneembodiment, the partial agonist may include buprenorphine or apharmaceutically acceptable salt thereof, while the antagonist includesnaloxone or a therapeutically acceptable salt thereof. It should beunderstood that the present invention is not limited to the use ofbuprenorphine and naloxone, and any agonist (or partial agonist) and anyantagonist may be incorporated into the present invention for use intreatment of drug addiction. The agonist and optional antagonist shouldbe selected from those agonists and antagonists that are useful intreating the particular narcotic dependence being treated.

As discussed above, the local pH of the dosage is preferably controlledto provide the desired release and/or absorption of the agonist andantagonist. Buprenorphine is known to have a pKa of about 8.42, whilenaloxone has a pKa of about 7.94. According to pH partition theory, onewould expect that saliva (which has a pH of about 6.5) would maximizethe absorption of both actives. However, it has been surprisinglydiscovered by the Applicants that by buffering the dosage to aparticular pH level, the optimum levels of absorption of the agonist andantagonist may be achieved. Desirably, the local pH of a compositionincluding an agonist and an antagonist is between about 2 to about 4,and most desirably is from 3 to 4. At this local pH level, the optimumabsorption of the agonist and the antagonist is achieved. As will bedescribed in more detail in the Examples below, controlling the local pHof the film compositions of the present invention provides a system inwhich the desired release and/or absorption of the components isbioequivalent to that of a similar Suboxone® tablet.

In one embodiment, the dosage form is a self-supporting film. In thisembodiment, the film dosage includes a polymer carrier matrix, atherapeutically effective amount of buprenorphine, an agonist. Thebuffer is preferably capable of providing a local pH of the compositionwithin a range that provides the desired level of absorption of thebuprenorphine. The resulting dosage is a film composition that allowsfor a rapid and effective release of buprenorphine into the oral cavityof the user. At the same time, the film composition preferably has asufficient adhesion profile, such that the film cannot easily be removedfrom the oral cavity of the user once it has been placed into thecavity. Full release of the buprenorphine preferably takes place withinless than about thirty minutes, and preferably remains in the oralcavity for at least 1 minute.

As explained above, while providing a pharmaceutically acceptable levelof an agonist is helpful in treating those with narcotic addiction, itmay be desirable to provide the buprenorphine in combination withnaloxone (an antagonist) so as to reduce the effect of the agonist andtherefore aid in reducing dependency of the narcotic. Therefore, it maybe desirable to combine the opioid agonist (or partial agonist) in thefilm composition with an opioid antagonist or a pharmaceuticallyacceptable salt thereof. The actives may be dispersed throughout thedosage separately or they may be combined together and dispersed intothe dosage. Most desirably the antagonist includes naloxone, but anysuitable basic antagonist may be selected as desired. The antagonist mayoptionally be water-soluble, so as to render separation of theantagonist and agonist difficult, thereby lessening the potential forabuse of the agonist.

As with a film including an agonist, the film including an agonist andan antagonist is desirably pH-controlled through the inclusion of abuffer. In such combination films, it has been discovered that the localpH of the film composition should preferably be in the range of about 2to about 4, and more preferably about 3 to about 4 so as to provide abioequivalent product as the commercially-available Suboxone® tablet.Most preferably the local pH of the film composition is about 3.5. Atthis local pH level, absorption of the buprenorphine is optimized whilethe absorption of the naloxone is inhibited.

The film may contain any desired level of self-supporting film formingpolymer, such that a self-supporting film composition is provided. Inone embodiment, the film composition contains a film forming polymer inan amount of at least 25% by weight of the composition. The film formingpolymer may alternatively be present in an amount of at least 50% byweight of the composition. As explained above, any film forming polymersthat impart the desired mucoadhesion and rate of film dissolution may beused as desired.

Any desired level of agonist and optional antagonist may be included inthe dosage, so as to provide the desired effect. In one particularembodiment, the film composition includes about 2 mg to about 16 mg ofagonist per dosage. More desirably, the film composition includes about4 mg to about 12 mg of agonist per dosage. If desired, the filmcomposition may include about 0.5 mg to about 5 mg of antagonist perdosage. More desirably, the film composition includes about 1 mg toabout 3 mg of antagonist per dosage. If an antagonist is incorporatedinto the film, the film composition may include the antagonist in aratio of about 6:1-2:1 agonist to antagonist. Most desirably, the filmcomposition contains about 4:1 agonist to antagonist per dosage. Forexample, in one embodiment, the dosage includes an agonist in an amountof about 12 mg, and includes an antagonist in an amount of about 3 mg.

The film compositions further desirably contains a buffer so as tocontrol the local pH of the film composition. Any desired level ofbuffer may be incorporated into the film composition so as to providethe desired local pH level. The buffer is preferably provided in anamount sufficient to control the release from the film and/or theabsorption into the body of the agonist and the optional antagonist. Ina desired embodiment, the film composition includes buffer in a ratio ofbuffer to agonist in an amount of from about 2:1 to about 1:5(buffer:agonist). The buffer may alternatively be provided in a 1:1ratio of buffer to agonist. As stated above, the film compositionpreferably has a local pH of about 2 to about 4, and most preferably hasa local pH of about 3.5. Any buffer system may be used as desired. Insome embodiments, the buffer may include sodium citrate, citric acid,and combinations thereof.

In this embodiment, the resulting film composition includes a polymermatrix, an agonist, and an optional antagonist, while the filmcomposition has a controlled local pH to the level desired. The bufferis preferably present in an amount to provide a therapeutically adequateabsorption of the agonist, while simultaneously limiting the absorptionof the antagonist. Controlling of the local pH allows for the desiredrelease and/or absorption of the components, and thus provides a moreuseful and effective dosage.

The film dosage composition may include a polymer carrier matrix, atherapeutically effective amount of agonist, a therapeutically effectiveamount of antagonist, and a buffering system. The buffering system mayinclude a buffer in addition to a solvent. The buffering systemdesirably includes a sufficient level of buffer so as to provide adesired local pH level of the film dosage composition.

In addition to a desired local pH level, the buffer preferably has abuffer capacity sufficient to maintain the ionization of the optionalantagonist during the time that the composition is in the oral cavity ofa user. Maintaining the ionization of the antagonist serves to limit theabsorption of the antagonist, and thus provide the desired control ofthe antagonist. While the ionization of the antagonist is limited, theionization of the agonist may not be so limited. As such, the resultingdosage form provides absorption of the agonist to the user, whilesufficiently reducing and/or preventing absorption of the antagonist. Bykeeping the antagonist ionized and the local pH at the optimum pH, theantagonist has limited if any absorption, but is still present shouldthe product be abused or taken via a different route of administration.However, when taken as administered, the antagonist has little to noeffect in blocking the agonist.

The film dosage composition including an agonist may be configured toprovide an in vivo plasma profile having a mean maximum plasmaconcentration (Cmax) in a desired range. It has been discovered by theApplicants that controlling the Cmax of the film composition allows oneto control the absorption of the active (such as an agonist) into theuser. The resulting film composition is more effective and suitable fordelivery to a user.

As explained, the film dosage composition provides a bioequivalentresult to a commercially available Suboxone® product. As will beexplained more in the Examples below, commercially available Suboxone®provides different absorption levels depending on the amount ofbuprenorphine and naloxone administered. The present invention desirablyprovides a film product providing bioequivalent release as that of theSuboxone® product. As with the Suboxone® product, the buprenorphine maybe present in an amount of from about 2 mg to about 16 mg per dosage,or, if desired about 4 mg to about 12 mg per dosage. Additionally, thenaloxone may be present in any desired amount, preferably at about 25%the level of buprenorphine. For example, an inventive film product mayhave 2 mg buprenorphine and 0.5 mg naloxone, 4 mg buprenorphine and 1 mgnaloxone, 8 mg buprenorphine and 2 mg naloxone, 12 mg buprenorphine and3 mg naloxone, 16 mg buprenorphine and 4 mg naloxone, or any similaramounts.

It has further been discovered that, by controlling the mean area underthe curve (AUC) value of the film composition, a more effective dosageform may be provided. As is described in more detail in the Examplesbelow, the inventive film composition preferably provides an AUC valueso as to provide a bioequivalent result as that provided by thecommercially available Suboxone® tablet. In one embodiment, the filmcomposition may include a mean AUCinf value of about 6.8 hr·ng/ml orgreater. Alternatively, the film composition may include a mean AUCinfvalue of from about 6.8 hr·ng/ml to about 66 hr·ng/ml.

As explained above, the film compositions may include naloxone, anantagonist. When the film composition includes a combination of agonistand antagonist, the film composition may be configured to provide aparticular Cmax and/or AUCinf for the antagonist. For example, when abuprenorphine agonist and a naloxone antagonist are incorporated intothe film composition, the naloxone may be configured to provide a Cmaxof less than about 400 pg/ml, less than about 318 pg/ml, less than about235 pg/ml, less than about 92 pg/ml or less than about 64 pg/ml. In suchfilms, the naloxone may provide a mean AUCinf value of less than about1030 hr·ng/ml.

In formulations which include an agonist in combination with anantagonist, the film composition may be prepared to provide a desiredCmax and/or AUCinf value for each of the agonist and antagonist. In oneembodiment, the film composition provides an in vivo plasma profilehaving a Cmax of less than about 6.4 ng/ml for the agonist and an invivo plasma profile having a Cmax of less than about 400 pg/ml for theantagonist. In such embodiments, the formulation may provide an AUCinfvalue of more than about 6.8 hr·ng/ml for the agonist. If desired, theformulation may provide an AUCinf value of less than about 1030 hr·pg/mlfor the antagonist. Such compositions may include the agonist and theantagonist in any desired amount, and in a preferred embodiment, thecomposition includes about 2 mg to about 16 mg of the agonist per dosageand about 0.5 mg to about 4 mg of the antagonist per dosage.

The present invention provides a method of treating narcotic dependencein a patient. In one embodiment, the patient is dependent on opioidnarcotics, but the patient may have a dependence on non-opioidnarcotics. Desirably, the patient is treated by providing a dosage tothe patient, which provides an effective release of actives butsimultaneously provides a suitable adhesion so that the dosage cannot beeasily removed. In one method of treatment, an orally dissolvable filmcomposition is provided to a patient.

Depending on the particular narcotic that the patient experiencesdependence upon, the film composition may include one or more particularactive components. In one embodiment, the film composition includes apolymer carrier matrix and a therapeutically effective amount of anagonist. Desirably the agonist is a partial agonist. For opioiddependency, the agonist may be an opioid agonist, such as buprenorphineor a pharmaceutically acceptable salt thereof. The film compositionpreferably includes a buffer in an amount sufficient to control thelocal pH of the film composition. Any buffer system may be used,including sodium citrate, citric acid, and combinations thereof. Incompositions solely including an agonist, the local pH of the filmcomposition is desirably about 5 to about 6.5, and most desirably thelocal pH is about 5.5. At this level, the absorption of the agonist ismost effective. To treat the dependency, the film composition isadministered to the patient, most desirably into the oral cavity of thepatient.

If desired, the composition may include a therapeutically effectiveamount of an antagonist, to prevent abuse of the agonist. A“therapeutically effective amount” of an antagonist is intended to referto an amount of the antagonist that may be useful in diverting abuse ofthe agonist by a user. The antagonist may be any desired antagonist, andin one embodiment includes naloxone or a pharmaceutically acceptablesalt thereof. The film composition is preferably administered to apatient through the oral cavity of the patient, but may be administeredin any desired means. The orally dissolvable film composition is thenallowed to dissolve in the oral cavity of the patient for a sufficienttime so as to release the active(s) therein. In some embodiments, thefilm composition may remain in the oral cavity for at least 30 seconds,and in some embodiments may remain in the oral cavity for at least 1minute. After the film composition is placed into the oral cavity of thepatient, the film preferably becomes sufficiently adhered so as torender its removal difficult. After the film composition has beenadministered to the patient, the active(s) are sufficiently releasedfrom the composition and allowed to take effect on the patient.

The film compositions of the present invention may be formed via anydesired process. Suitable processes are set forth in U.S. Pat. Nos.7,425,292 and 7,357,891, the entire contents of which are incorporatedby reference herein. In one embodiment, the film dosage composition isformed by first preparing a wet composition, the wet compositionincluding a polymeric carrier matrix, a therapeutically effective amountof an agonist, and a buffer in an amount sufficient to control the localpH of the composition to a desired level. The wet composition is castinto a film and then sufficiently dried to form a self-supporting filmcomposition. The wet composition may be cast into individual dosages, orit may be cast into a sheet, where the sheet is then cut into individualdosages. The agonist may be a partial agonist. If desired, the wetcomposition may include a therapeutically effective amount of anantagonist.

The agonist and the optional antagonist are preferably selected to treata particular narcotic dependency. For opioid dependency, for example,the agonist may include buprenorphine or a pharmaceutically acceptablesalt thereof, while the antagonist may include naloxone or apharmaceutically acceptable salt thereof. The local pH of the filmcomposition is desirably maintained at about 2 to about 4.

EXAMPLES Example 1 Composition of Buprenorphine/Naloxone Films atVarious Strengths

Film strips including a combination of buprenorphine and naloxone wereprepared. Four different strength film compositions were prepared, whichinclude a ratio of buprenorphine to naloxone of 16/4, 12/3, 8/2, and2/0.5. The compositions are summarized in Table 1 below.

TABLE 1 Various Compositions of Film Dosages Buprenorphine/ NaloxoneFilms Unit Formula (mg per film strip) Buprenorphine/ Naloxone RatiosComponents 16/4 12/3 8/2 2/0.5 Active Components Buprenorphine HCl 17.2812.96 8.64 2.16 Naloxone HCl Dihydrate 4.88 3.66 2.44 0.61 InactiveComponents Polyethylene Oxide, NF 27.09 20.32 13.55 — (MW 200,000)Polyethylene Oxide, NF 12.04 9.03 6.02 19.06 (MW 100,000) PolyethyleneOxide, NF 4.82 3.62 2.41 2.05 (MW 900,000) Maltitol, NF 12.04 9.03 6.025.87 Flavor 6.0 4.5 3.0 2.4 Citric Acid, USP 5.92 4.44 2.96 2.96 HPMC4.22 3.16 2.11 2.34 Ace-K 3.0 2.25 1.5 1.2 Sodium Citrate, anhydrous2.68 2.01 1.34 1.34 Colorant 0.03 0.02 0.01 0.01 Total (mg) 100 75 50 40

Example 2 Absorption Studies for Suboxone® Products

Various film and tablet products were prepared and tested for absorptiondata, including Cmax and AUC absorption levels. The products testedincluded Suboxone® tablets made with either 2 mg or 16 mg buprenorphineas well as either 0.5 mg or 4.0 mg naloxone. For 16 mg buprenorphinetablets, two 8 mg buprenorphine tablets were combined together toprovide the level of components of a 16 mg buprenorphine tablet. Ininstances where a 12 mg buprenorphine tablet was evaluated, this dosagewas obtained by combining one 8 mg buprenorphine tablet and two 2 mgbuprenorphine tablets. These products were tested for absorption levels,with the amounts listed in Table 2 below.

TABLE 2 Absorption Data for Suboxone ® products Sample C max AUCBuprenorphine (2 mg) Suboxone ®  0.780 ng/ml  6.789 hr * ng/ml TabletNaloxone (0.5 mg) Suboxone ® Tablet  51.30 pg/ml 128.60 hr * pg/mlBuprenorphine (16 mg) Suboxone ®  4.51 ng/ml  44.99 hr * ng/ml TabletNaloxone (4 mg) Suboxone ® Tablet 259.00 pg/ml 649.60 hr * pg/ml

Using the data from Table 2, absorption data for the Suboxone® tabletsfor other levels of buprenorphine and naloxone are set forth in Table 2Abelow.

TABLE 2A Extrapolated Absorption Data for Suboxone ® products Sample Cmax AUC Buprenorphine (4 mg) Suboxone ®  1.35 ng/ml 12.25 hr * ng/mlTablet Naloxone (1 mg) Suboxone ® Tablet  80.97 pg/ml   203 hr * pg/mlBuprenorphine (8 mg) Suboxone ®  2.29 ng/ml 23.17 hr * ng/ml TabletNaloxone (2 mg) Suboxone ® Tablet 140.31 pg/ml 351.8 hr * pg/mlBuprenorphine (12 mg) Suboxone ®  3.23 ng/ml 34.08 hr * ng/ml TabletNaloxone (3 mg) Suboxone ® Tablet  199.7 pg/ml 500.6 hr * pg/ml

Example 3 Evaluation of Bioequivalence of Suboxone® Tablets

Using the data generated for Suboxone® tablets in Table 2 above,acceptable bioequivalence ranges are generated to provide an equivalenttreatment level as the Suboxone® tablet. As currently understood, aproduct provides a bioequivalent effect if it provides absorption levelsbetween about 80% to about 125% of the Suboxone® tablet. Absorption inthis range is considered to be bioequivalent.

TABLE 3 Acceptable Bioequivalence Ranges for Suboxone ® Tablets (80 to125%) Description of Sample C max AUC Buprenorphine 0.624 to 0.975 ng/ml5.431 to 8.486 hr * ng/ml 2 mg Naloxone 41.04 to 64.13 pg/ml 102.88 to160.75 hr * pg/ml 0.5 mg Buprenorphine 3.608 to 5.638 ng/ml 35.992 to56.238 hr * ng/ml 16 mg Naloxone 4 mg 207.20 to 323.75 pg/ml 519.68 to812.00 hr * pg/ml

Thus, to be considered bioequivalent to the Suboxone® tablet, the Cmaxof buprenorphine is between about 0.624 and 5.638, and the AUC ofbuprenorphine is between about 5.431 to about 56.238. Similarly, to beconsidered bioequivalent to the Suboxone® tablet, the Cmax of naloxoneis between about 41.04 to about 323.75, and the AUC of naloxone isbetween about 102.88 to about 812.00.

Example 4 Absorption Studies for Film Products at pH 3.5

Various film products were prepared and tested for absorption data,including Cmax and AUC absorption levels. The products tested includedinventive film strips, the film strips having either 2 mg or 16 mgbuprenorphine as well as either 0.5 mg or 4.0 mg naloxone. Theseproducts were tested for absorption levels, with the amounts listed inTable 4 below.

TABLE 4 Absorption Data for inventive film products at pH 3.5 Sample Cmax AUC Buprenorphine (2 mg) Sublingual Film  0.947 ng/ml  7.82 hr *ng/ml Naloxone (0.5 mg) Sublingual Film  51.10 pg/ml 128.60 hr * pg/mlBuprenorphine (16 mg) Sublingual Film  5.47 ng/ml  55.30 hr * ng/mlNaloxone (4 mg) Sublingual Film 324.00 pg/ml 873.60 hr * pg/ml

As can be seen, in this experiment, the values for buprenorphineabsorbance were squarely in the bioequivalence range evaluated above.The inventive films were therefore determined to have provided abioequivalent absorption of buprenorphine at a local pH of 3.5 as thecommercially available Suboxone® tablet. The values for absorption ofnaloxone were very close to the bioequivalent range of Suboxone®. Theslightly higher absorption of Naloxone was not due to the local pH butrather to the amount of buffer (buffer capacity as discussed in theapplication). This is confirmed by the fact that the lower 2/0.5 mg doseis in range for the Naloxone and this is due to the higher buffercapacity for the 2/0.5 dose as pointed out in the buffer capacity chart.

Example 5 Preparation of Films for In Vivo Study

Film dosages were prepared for use in an in vivo study to determine thebioavailability of buprenorphine/naloxone tablets and film formulations.Specifically, the films were tested to determine whether the filmprovides a bioequivalent effect to that of a tablet formulation.

Three film formulations including 8 mg buprenorphine and 2 mg naloxonewere prepared, each being buffered to a different pH. The first film didnot include any buffer, providing a local pH of about 6.5. The secondwas buffered to a local pH level of about 3-3.5. The third was bufferedto a local pH value of about 5-5.5. The formulations are set forth inTable 5 below.

TABLE 5 Formulations of Test Films at Various pH Levels Test Test Testformulation 1 formulation 2 formulation 3 8 mg/2 mg 8 mg/2 mg 8 mg/2 mgpH = 6.5 pH = 3-3.5 pH = 5-5.5 Component % w/w Mg/film % w/w Mg/film %w/w Mg/film Buprenorphine 21.61 8.64 17.28 8.64 17.28 8.64 HCl NaloxoneHCl 6.10 2.44 4.88 2.44 4.88 2.44 Dihydrate Polymer 5.05 2.02 4.82 2.414.82 2.41 Polymer 28.48 11.39 27.09 13.55 27.09 13.55 Polymer 12.65 5.0612.04 6.02 12.04 6.02 Polymer 4.43 1.77 4.22 2.11 4.22 2.11 Sweetener12.65 5.06 12.04 6.02 12.04 6.02 Sweetener 3 1.2 3 1.5 3 1.5 Flavor 62.4 6 3 6 3 Citric acid 0 0 5.92 2.96 2.51 1.26 Sodium citrate 0 0 2.681.34 6.08 3.04 FD&C yellow 0.025 0.01 0.03 0.02 0.03 0.02 #6 Total 10040 100 50 100 50

Example 6 Analysis of In Vivo Absorption of Film Having a pH of 6.5

The film dosage composition of film having a local pH of 6.5 wasanalyzed. Specifically, Test Formulation 1, as prepared in Example 5 wasanalyzed in vivo to determine the absorption of buprenorphine and ofnaloxone. The comparative film was compared to the absorption ofbuprenorphine and of naloxone provided by a one dose tablet (Suboxone®).The test film was compared to determine whether it provided abioequivalent effect as the tablet product.

The results for Test Formulation 1, which had a local pH of about 6.5,as compared to the one dose tablet, are set forth in Tables 6 and 7below.

TABLE 6 Buprenorphine In Vivo Absorption Data for Test Formulation 1Suboxone ® Test Formulation 1 sublingual (pH = 6.5) Parameter n Mean SDCV % n Mean SD CV % T_(max) (hr) 15 1.60 0.47 29.41 15 1.50 0.62 41.23C_(max) 15 2.27 0.562 24.77 15 2.60 0.872 33.53 (ng/mL) AUC_(last) 1527.08 10.40 38.41 15 31.00 12.93 41.72 (hr * ng/mL) AUC_(inf) 15 29.5811.15 37.68 15 33.37 13.88 41.61 (hr * ng/mL) T_(1/2) (hr) 15 44.7620.86 46.60 15 40.73 14.93 36.66

TABLE 7 Naloxone In Vivo Absorption Data for Test Formulation 1 TestFormulation 1 Suboxone ® sublingual (pH = 6.5) Parameter n Mean SD CV %n Mean SD CV % T_(max) (hr) 15 0.90 0.23 25.32 15 0.68 0.18 25.75C_(max) 15 94.6 39.1 41.33 15 410 122 29.75 (pg/mL) AUC_(last) 15 297.1120.7 40.62 15 914.8 158.1 17.29 (hr * pg/mL) AUC_(inf) 15 306.1 122.640.06 15 924.2 158.8 17.18 (hr * pg/mL) T_(1/2) (hr) 15 6.62 2.60 39.2615 6.86 2.08 30.27

As can be seen, the in vivo data indicates that buprenorphine isabsorbed very well from the film formulation at a local pH of 6.5, andmatched closely the absorption seen in the Suboxone® one dose tablet.However, the absorption was also maximized for the naloxone, which wasundesirable. It was determined that a film having a combination ofbuprenorphine and naloxone and a local pH of 6.5 did not provide abioequivalent effect as the Suboxone® tablet for both buprenorphine andnaloxone.

Example 7 Analysis of In Vivo Absorption of Film Having a pH of 5-5.5

Having determined the absorption of buprenorphine and naloxone in filmhaving a local pH of 6.5, a film dosage composition of film having alocal pH of 5-5.5 was analyzed. Specifically, Test Formulation 3, asprepared in Example 5 was analyzed in vivo to determine the absorptionof buprenorphine and of naloxone. The comparative films were compared tothe absorption of buprenorphine and of naloxone provided by theSuboxone® one dose tablet. The test film was compared to determinewhether it provided a bioequivalent effect as the Suboxone® tablet.

The results for Test Formulation 3, which had a local pH of about 5-5.5,as compared to the Suboxone® tablet, are set forth in Tables 8 and 9below.

TABLE 8 Buprenorphine In Vivo Absorption Data for Test Formulation 3Test Formulation 3 Suboxone ® sublingual (pH = 5-5.5) Parameter n MeanSD CV % n Mean SD CV % T_(max) (hr) 15 1.60 0.47 29.41 14 1.50 0.4328.50 C_(max) 15 2.27 0.562 24.77 14 3.47 1.57 45.40 (ng/mL) AUC_(last)15 27.08 10.40 38.41 14 33.25 16.01 48.16 (hr * ng/mL) AUC_(inf) 1529.58 11.15 37.68 13 38.34 15.38 40.13 (hr * ng/mL) T_(1/2) (hr) 1544.76 20.86 46.60 13 41.71 17.70 42.42

TABLE 9 Naloxone In Vivo Absorption Data for Test Formulation 3 TestFormulation 3 Suboxone ® sublingual (pH = 5-5.5) Parameter n Mean SD CV% n Mean SD CV % T_(max) (hr) 15 0.90 0.23 25.32 14 0.98 0.62 63.51C_(max) 15 94.6 39.1 41.33 14 173 84.5 48.79 (pg/mL) AUC_(last) 15 297.1120.7 40.62 14 455.2 195.5 42.94 (hr * pg/mL) AUC_(inf) 15 306.1 122.640.06 13 474.4 203.1 42.81 (hr * pg/mL) T_(1/2) (hr) 15 6.62 2.60 39.2613 9.45 6.90 73.00

As can be seen, the in vivo data indicated that the absorption ofbuprenorphine increased as the local pH level decreased. It appearedthat by decreasing the local pH from 6.5 to 5.5, the absorption ofbuprenorphine was being moved to a level further away from that of theone dose tablet. In addition, the naloxone values did not provide abioequivalent result as the one dose tablet. Thus, it was determinedthat the film having a local pH of 5.5 did not provide a bioequivalentresult as that of the Suboxone® tablet for both buprenorphine andnaloxone.

It was noted that by reducing the local pH of the film to a level of5.5, there would be provided an increased level of absorption ofbuprenorphine. Thus, it may be desirable to buffer a film compositionincorporating buprenorphine itself to a level of about 5.5 to provide anincreased absorption.

Example 8 Analysis of In Vivo Absorption of Film Having a pH of 3-3.5

Having determined the absorption of buprenorphine and naloxone in filmshaving a local pH of 6.5 and 5.5, a film dosage composition of filmhaving a local pH of about 3-3.5 was analyzed. It was assumed that theabsorption of buprenorphine would continue to be increased as it haddemonstrated at a local pH of 5.5. Thus, it was assumed that at a localpH of 3.5, the film would not be bioequivalent to that of the tablet.

Specifically, Test Formulation 2, as prepared in Example 5, was analyzedin vivo to determine the absorption of buprenorphine and of naloxone.The comparative films were compared to the absorption of buprenorphineand of naloxone provided by the Suboxone® one dose tablet. The test filmwas compared to determine whether it provided a bioequivalent effect asthe tablet product.

The results for Test Formulation 2, which had a local pH of about 3-3.5,as compared to the Suboxone® tablet, are set forth in Tables 10 and 11below.

TABLE 10 Buprenorphine In Vivo Absorption Data for Test Formulation 2Suboxone ® Test Formulation 2 sublingual (pH = 3-3.5) Parameter n MeanSD CV % n Mean SD CV % T_(max) (hr) 15 1.60 0.47 29.41 14 1.68 0.5834.68 C_(max) 15 2.27 0.562 24.77 14 2.68 0.910 33.99 (ng/mL) AUC_(last)15 27.08 10.40 38.41 14 29.73 12.05 40.54 (hr * ng/mL) AUC_(inf) 1529.58 11.15 37.68 14 31.45 12.98 41.26 (hr * ng/mL) T_(1/2) (hr) 1544.76 20.86 46.60 14 30.03 13.95 46.46

TABLE 11 Naloxone In Vivo Absorption Data for Test Formulation 2 TestFormulation 2 Suboxone ® sublingual (pH = 3-3.5) Parameter n Mean SD CV% n Mean SD CV % T_(max) (hr) 15 0.90 0.23 25.32 14 0.84 0.19 22.19C_(max) 15 94.6 39.1 41.33 14 130 72.9 56.04 (pg/mL) AUC_(last) 15 297.1120.7 40.62 14 362.2 155.9 43.03 (hr * pg/mL) AUC_(inf) 15 306.1 122.640.06 12 350.4 142.3 40.61 (hr * pg/mL) T_(1/2) (hr) 15 6.62 2.60 39.2612 8.07 4.75 58.84

As can be seen, the in vivo data indicated that the absorption ofbuprenorphine was substantially bioequivalent to that of the one dosetablet when the film composition local pH was lowered to about 3-3.5.This result was surprising as it did not appear to follow the pHpartition theory. Further, at a local pH of about 3-3.5, it was seenthat the absorption of naloxone was substantially bioequivalent to thatof the one dose tablet.

Thus, it was determined that the film product including buprenorphineand naloxone at a local pH of 3-3.5 was substantially bioequivalent tothat of the Suboxone® one dose tablet.

Example 9 Normalized Values for Naloxone in Films and Tablets

Various film compositions including buprenorphine and naloxone in 8/2 mgand 2/0.5 mg dosages, and having different local pH values from 6.5 to3.5, were prepared and analyzed. The data was normalized and compared tothe one dose tablet. The results are set forth in Table 12 below.

TABLE 12 Normalized Values for Naloxone Film Compared to Tablet RatioCitric Mg Acid(mg)/ Dose (mg) AUC Citric Naloxone pHBuprenorphine/Naloxone (Normalized) Cmax Acid (mg) 6.5 8/2 3.02 4.331.34 0.67 5.5 8/2 1.55 1.83 1.34 0.67 3.5 8/2 1.14 1.37 1.34 0.67 3.5  2/0.5 0.98 0.90 1.34 2.68 5.5   2/0.5 1.41 1.41 1.34 2.68

The data indicates that not only is the local pH of significantimportance, but the amount of buffer present in the formula is alsoimportant. The improvement from the 8/2 dose to the 2/0.5 dose (at alocal pH of 3.5) demonstrates this importance. The 8/2 dose has a ratioof buffer/naloxone of 0.67, and this dose provided borderline acceptablebioequivalent results. In contrast, the 2/0.5 dose has a ratio ofbuffer/naloxone of 2.68, and provides a more bioequivalent absorptionvalue than the 8/2 dose.

In fact, the data shows that the 2/0.5 dose at a local pH of 3.5 had aneven lower buccal absorption than the one dose tablet, as seen from thenormalized values for the AUC and Cmax. This demonstrates that even lessabsorption of the naloxone occurs for the film formulation at a local pHof 3.5 than the tablet formulation. Given the goal of reducing theabsorption of naloxone, it appears that the film product buffered at alocal pH of 3.5 with a buffer ratio of buffer/Naloxone of 2.68 provideseven better results than the Suboxone® tablet formulation.

What is claimed is:
 1. A film dosage composition comprising: a. A polymeric carrier matrix; b. A therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; c. A therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof; and d. A buffer in an amount to provide a local pH for said composition of a value sufficient to optimize absorption of said buprenorphine, wherein said local pH is from about 3 to about 3.5 in the presence of saliva.
 2. The composition of claim 1, wherein said film dosage composition provides a bioequivalent absorption of buprenorphine to that of a tablet having an equivalent amount of buprenorphine or a pharmaceutically acceptable salt thereof.
 3. The composition of claim 1, wherein said polymeric carrier matrix comprises at least one polymer in an amount of at least 25% by weight of said composition.
 4. The composition of claim 1, wherein said buffer is present in an amount of from about 2:1 to about 1:5 by weight of buffer to buprenorphine.
 5. The composition of claim 1, wherein said polymeric carrier matrix comprises at least one self-supporting film forming polymer.
 6. The film dosage composition of claim 1, wherein said buprenorphine is present in an amount of from about 2 mg to about 16 mg per dosage.
 7. The film dosage composition of claim 1, wherein said buffer comprises sodium citrate, citric acid, and combinations thereof.
 8. The film dosage composition of claim 1, wherein said buffer comprises acetic acid, sodium acetate, and combinations thereof.
 9. A method of treating narcotic dependence of a user, comprising the steps of: a. providing a composition comprising: i. A polymeric carrier matrix; ii. A therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; iii. A therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof; and iv. A buffer in an amount to provide a local pH of about 3 to about 3.5 for said composition of a value sufficient to optimize absorption of said buprenorphine and also sufficient to inhibit absorption of said naloxone; and b. administering said composition to the oral cavity of a user.
 10. The composition of claim 9, wherein said method provides a bioequivalent absorption of buprenorphine to that of a tablet having an equivalent amount of buprenorphine or a pharmaceutically acceptable salt thereof.
 11. The method of claim 9, wherein said film dosage composition is administered to the user through buccal administration, sublingual administration, and combinations thereof.
 12. The method of claim 9, wherein said film dosage composition remains in the oral cavity of the user for a period of at least 1 minute.
 13. The method of claim 9, wherein said film dosage composition remains in the oral cavity of the user for a period of between about 1 and 1.5 minutes.
 14. The method of claim 9, wherein said film dosage composition remains in the oral cavity of the user for a period of up to 3 minutes.
 15. An orally dissolving film formulation comprising buprenorphine and naloxone, wherein said formulation provides an in vivo plasma profile having a Cmax of between about 0.624 ng/ml and about 5.638 ng/ml for buprenorphine and an in vivo plasma profile having a Cmax of between about 41.04 pg/ml to about 323.75 pg/ml for naloxone.
 16. The formulation of claim 15, wherein said formulation provides a mean AUC of between about 5.431 hr·ng/ml to about 56.238 hr·ng/ml for buprenorphine.
 17. The formulation of claim 15, wherein said formulation provides a mean AUC of between about 102.88 hr·pg/ml to about 812.00 hr·pg/ml for naloxone.
 18. The formulation of claim 15, wherein said formulation comprises about 2 to about 16 mg of buprenorphine or a salt thereof.
 19. The formulation of claim 15, wherein said formulation comprises about 0.5 to about 4 mg of naloxone or a salt thereof. 